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Open Access 01-10-2019 | Alzheimer's Disease | Original Paper

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation

Authors: Maxime Sartori, Tiago Mendes, Shruti Desai, Alessia Lasorsa, Adrien Herledan, Nicolas Malmanche, Petra Mäkinen, Mikael Marttinen, Idir Malki, Julien Chapuis, Amandine Flaig, Anaïs-Camille Vreulx, Marion Ciancia, Philippe Amouyel, Florence Leroux, Benoit Déprez, François-Xavier Cantrelle, Damien Maréchal, Laurent Pradier, Mikko Hiltunen, Isabelle Landrieu, Devrim Kilinc, Yann Herault, Jocelyn Laporte, Jean-Charles Lambert

Published in: Acta Neuropathologica | Issue 4/2019

Abstract

The bridging integrator 1 gene (BIN1) is a major genetic risk factor for Alzheimer’s disease (AD). In this report, we investigated how BIN1-dependent pathophysiological processes might be associated with Tau. We first generated a cohort of control and transgenic mice either overexpressing human MAPT (TgMAPT) or both human MAPT and BIN1 (TgMAPT;TgBIN1), which we followed-up from 3 to 15 months. In TgMAPT;TgBIN1 mice short-term memory deficits appeared earlier than in TgMAPT mice; however—unlike TgMAPT mice—TgMAPT;TgBIN1 mice did not exhibit any long-term or spatial memory deficits for at least 15 months. After killing the cohort at 18 months, immunohistochemistry revealed that BIN1 overexpression prevents both Tau mislocalization and somatic inclusion in the hippocampus, where an increase in BIN1–Tau interaction was also observed. We then sought mechanisms controlling the BIN1–Tau interaction. We developed a high-content screening approach to characterize modulators of the BIN1–Tau interaction in an agnostic way (1,126 compounds targeting multiple pathways), and we identified—among others—an inhibitor of calcineurin, a Ser/Thr phosphatase. We determined that calcineurin dephosphorylates BIN1 on a cyclin-dependent kinase phosphorylation site at T348, promoting the open conformation of the neuronal BIN1 isoform. Phosphorylation of this site increases the availability of the BIN1 SH3 domain for Tau interaction, as demonstrated by nuclear magnetic resonance experiments and in primary neurons. Finally, we observed that although the levels of the neuronal BIN1 isoform were unchanged in AD brains, phospho-BIN1(T348):BIN1 ratio was increased, suggesting a compensatory mechanism. In conclusion, our data support the idea that BIN1 modulates the AD risk through an intricate regulation of its interaction with Tau. Alteration in BIN1 expression or activity may disrupt this regulatory balance with Tau and have direct effects on learning and memory.

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Title: BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation
Authors: Maxime Sartori
Tiago Mendes
Shruti Desai
Alessia Lasorsa
Adrien Herledan
Nicolas Malmanche
Petra Mäkinen
Mikael Marttinen
Idir Malki
Julien Chapuis
Amandine Flaig
Anaïs-Camille Vreulx
Marion Ciancia
Philippe Amouyel
Florence Leroux
Benoit Déprez
François-Xavier Cantrelle
Damien Maréchal
Laurent Pradier
Mikko Hiltunen
Isabelle Landrieu
Devrim Kilinc
Yann Herault
Jocelyn Laporte
Jean-Charles Lambert
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: Acta Neuropathologica / Issue 4/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02017-9

At a glance: The STEP trials

Springer Medicine

BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr³⁴⁸ phosphorylation

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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